Organophosphorus (OP) compounds are deadly chemicals that exert their intoxicating
effects through the irreversible inhibition of acetylcholinesterase (AChE). In addition
to an excess of peripheral ailments, OP intoxication induces status epilepticus (SE)
which if left untreated may lead to permanent brain damage or death. Benzodiazepines
are typically the primary therapies for OP-induced SE, but these drugs lose efficacy
as treatment time is delayed. The CounterACT Neurotherapeutic Screening (CNS) Program
was therefore established by the National Institutes of Health (NIH) to discover novel
treatments that may be administered adjunctively with the currently approved medical
countermeasures for OP-induced SE in a delayed treatment scenario. The CNS program
utilizes in vivo EEG recordings and Fluoro-JadeB (FJB) histopathology in two established
rat models of OP-induced SE, soman (GD) and diisopropylfluorophosphate (DFP), to evaluate
the anticonvulsant and neuroprotectant efficacy of novel adjunct therapies when administered
at 20 or 60 min after the induction of OP-induced SE. Here we report the results of
multiple compounds that have previously shown anticonvulsant or neuroprotectant efficacy
in other models of epilepsy or trauma. Drugs tested were ganaxolone, diazoxide, bumetanide,
propylparaben, citicoline, MDL-28170, and chloroquine. EEG analysis revealed that
ganaxolone demonstrated the most robust anticonvulsant activity, whereas all other
drugs failed to attenuate ictal activity in both models of OP-induced SE. FJB staining
demonstrated that none of the tested drugs had widespread neuroprotective abilities.
Overall these data suggest that neurosteroids may represent the most promising anticonvulsant
option for OP-induced SE out of the seven unique mechanisms tested here. Additionally,
these results suggest that drugs that provide significant neuroprotection from OP-induced
SE without some degree of anticonvulsant activity are elusive, which further highlights
the necessity to continue screening novel adjunct treatments through the CNS program.